1. Description of the problem

Definitions

Hypertension is defined as blood pressure (BP) that exceeds the 95th percentile for values stratified by age, gender and stature. Severe hypertension is defined as BP that exceeds the 99th percentile. These definitions are reiterated in the 2004 Fourth Task Force Report, and in that report, it is stated that BPs that are greater than 5 mmHg above the 99th percentile require a prompt response.

Hypertensive emergency or crisis implies a threat to the integrity of target organs, such as the central nervous system (CNS), cardiovascular system and renal system.

Hypertensive urgency implies elevated readings without immediate threat to the integrity of the target organs.

There is no specific BP number that defines hypertensive crisis or emergency, so it is important that the examining physician carefully assess the patient and put the BP reading into context.

When there is overt target organ damage in the setting of an elevated BP, defining hypertensive emergency is straightforward. However, it makes sense to broaden the definition of hypertensive emergency to include patients who, at the time of presentation, or who, in the near future, are likely to manifest the signs of target organ involvement.

This seems to be a prudent approach, and yet some patients may be managed for this condition who might have never progressed, but given that rapid changes with acute and severe clinical deterioration can occur, it stands to reason that one might avoid potential complications by being more proactive.

It is also important to keep the patient's clinical context in mind when assessing for hypertensive emergency. If a child has pre-existing hypertension because of a chronic illness or condition, higher degrees of BP elevation may be tolerated. The absolute value of BP at the time of evaluation is important, yet just as important are the pre-exisiting BP ranges of the individual patient, the chronicity of the hypertension, and the acuteness and degree of BP elevation over baseline.

What every clinician needs to know

BP measurement is a key element that must be taken into account, for if the measurement technique results in misleading readings, there may be unnecessary interventions taken. The standards by which we compare to normal readings were all taken with standardized conditions with the patient in a seated position, using the child's right arm at heart level. A BP cuff that is too small may falsely elevate the reading, and there is debate as to whether a cuff that is too large will provide a falsely low reading.

If a child's arm falls between sizes, then one should use the larger of the two cuffs. The width of the cuff inflatable bladder ought to be about 40% of the arm circumference at a point midway between the acromion and olecranon processes. The bladder length ought to encircle 80% to 100% of the arm circumference.

Oscillometric devices are often utilized to measure BP, especially in the emergency department and inpatient settings. It is recommended the elevated readings by oscillometry be confirmed with auscultatory methods.

The use of tables of normative BP data in children will provide a precise classification of BP. These tables are stratified by age, gender and stature. To use these tables, one needs to have the child's height, which is not always readily available in an acute care setting. If the child's actual height is not available, one may use the BP limits for the average (50th percentile) for age and gender of the child as a means of initially evaluating BP.

The idea of staging BP can assist in the determination of which children may require more immediate attention for hypertension. BP readings can vary considerably, and the difference between the 95th and 99th percentiles of only 7 to 10 mmHg is not large enough to adequately distinguish mild from more severe hypertension.

By convention, stage 1 hypertension is defined as BP levels ranging from the 95th percentile to 5 mmHg above the 99th percentile. Patients with BP in this range who are asymptomatic should be referred for repeat BP measurement within 1 to 2 weeks at the primary care provider's office.

The designation of stage 2 hypertension is when the BP levels are greater than 5 mmHg above the 99th percentile. This degree of hypertension requires more immediate attention with prompt evaluation, and if persistent, may even be considered an indication for the initiation of antihypertensive therapy.

Clinical features of the condition

Differential diagnosis of hypertension will depend to a great extent upon the age of the patient. Because of the recent increase in the prevalence of childhood obesity, primary or essential hypertension is expected to be increased in all age groups. A general rule of thumb, however, is that the higher the BP, the more likely there is a secondary cause for the hypertension.

Early in life, renovascular disease, renal parenchymal disease (renal anomalies) and coarctation should be considered.

In early childhood, renal parenchymal disease (ie, glomerulonephritis) is one of the more common etiologies of hypertension, but renovascular disease and coarctation of the aorta must be considered.

In school-aged children, essential hypertension can be a possible cause, but less so than renal parenchymal and renovascular disease. Beyond 12 years of age, essential hypertension is the most common cause of hypertension, although it does not commonly present as a hypertension emergency or urgency.

At any age, endocrine causes of hypertension can be considered, although they are not that common. Hyperthyroidism, Cushing disease and pheochromocytoma are uncommon, but may be considered at any age group. Catecholamine excess with neuroblastoma may also be linked with hypertension. Other etiologies of severe hypertension include increased intracranial pressure, some medications (steroids, beta-agonists, stimulants), and drugs of abuse like cocaine and amphetamines.

Key management points

Key management issues related to severely elevated BP are the availability of the appropriately sized pieces of equipment to do the measurements accurately, recognition of the concept that for children and adolescents there are age, gender and stature adjusted normative data for BP values, and a knowledge about the use of antihypertensive medications in this age group.

Clinical assessment includes a history, physical examination and investigations. The goal of the initial history and examination should be to try to determine a cause and the severity of the child's hypertension. Additionally, one must assess for complications of the underlying disease process. Emergently, one must assess airway, breathing and circulation, then history and physical examination can take place.

It is also important to recognize that some children presenting with raised BP may be previously known to have hypertension and may be on medication for it. Details of any antihypertensive management and compliance with medications should be assessed. Recent withdrawal or changes in medications may result in rebound or recurrent rises in BP.

2. Emergency Management

As with all emergencies, assessment of the patient's clinical status will include assessment of airway, breathing and circulation. After that set of steps, getting a detailed history and a complete physical examination are important. In assessing the patient, one is looking not only for a potential explanation for the elevated BP, but also for any evidence of target organ disease.

Most of the time, the child with mildly elevated to moderately elevated BP can be managed in the outpatient setting. These patients should be sent back to their source of primary care to have BP rechecked and to see if there is confirmation of the problem.

In the setting of severely elevated BP, the focus ought to be on the safe reduction of BP in a timely manner, as well as the identification and treatment of any secondary complications. A true hypertensive emergency should be managed in the hospital setting, and it may take place in the intensive care unit or the pediatric ward, as indicated by the patient's clinical status and the local resources.

It is generally recommended that BP be reduced by no more than 25% in the first 6 to 8 hours. There is good reason for a conservative approach to the problem, because in longstanding hypertension, the range of BP over which cerebrovascular autoregulation occurs shifts upward.

With prolonged hypertension, vascular endothelial damage, tissue inflammation and oxidative stress combine to make the vasculature less responsive to changes in BP. If there is a precipitous drop in BP, there may be dangerously low cerebral perfusion. After the BP is initially stabilized, it may be lowered over the course of the next several days.

In a true hypertensive emergency, the patient needs to have adequate intravenous (IV) access, cardiopulmonary monitoring and close BP monitoring. Giving medications by the IV route may be preferable in the setting of a hypertensive emergency so that accurate titration of dose can achieve the expected response. Enteral medications may be absorbed less reliably, and the timing of effect may not be as predictable as IV medications.

Most specific medications are chosen based on their availability, the physician's familiarity with use of the drug and the underlying pathophysiology of the hypertensive process. Side effects should be considered as well.

Drugs and dosages

Oral medications

Nifedipine: Use of this short-acting oral calcium channel blocker in children with severe hypertension is somewhat controversial. There have been reports in adults of adverse cardiac and neurologic sequelae with its administration, and those have led to a moratorium on its use in hypertensive adults. These same sequelae have not been reported in children, but there have been reports of rebound hypertension with adverse outcomes. Many pediatric nephrologists continue to use it for treatment of moderate to severe hypertension in children.

Two retrospective studies of 117 and 166 children, respectively, treated with nifedipine have concluded that the drug is safe at an initial dose of 0.25mg/kg and a maximum dose of 10 mg. Duration of action is about 6 hours. It has been administered sublingually in the past, but that practice has been discouraged due to unpredictable absorption. The liquid-filled capsule may be bitten and swallowed for faster absorption, or the liquid may be aspirated with a small needle into a syringe to administer smaller doses. Prudent use of this agent as a bridge to more definitive therapy may be indicated.

IV intermittently dosed medications

Labetalol: This agent is a combined alpha1 and β-adrenergic receptor blocker. It begins to have an effect within 2 to 5 minutes after administration, and it may last as long as 2 to 4 hours. What makes it different from pure β-blockers, which decrease cardiac output without affecting systemic vascular resistance, is that labetalol maintains perfusion by balancing a modest reduction in heart rate with a lowering of systemic vascular resistance through vasodilatation, keeping peripheral blood flow relatively stable.

Labetalol also allows for maintenance of coronary, renal and cerebral blood flow. It can be given as bolus doses or by continuous infusion. Boluses of 0.2 to 1mg/kg are used, and they may be repeated every 10 to 15 minutes. Continuous infusion rates range from 0.25 to 3 mg/kg/h, although dosing recommendations vary widely.

Because of the β-blockade effect, labetalol should not be used in patients with asthma or other obstructive lung disease, because bronchospasm may be precipitated. It should also be used with caution in patients with left ventricular heart failure because of its negative ionotropic and dromotropic effects.

Labetalol should also be used with caution in patients with diabetes, because β-blockers may blunt the response to hypoglycemia, and the signs and symptoms of low blood sugar may be masked.

Hydralazine: This agent is an arterial vasodilator, and its mechanism of action is not well understood. It has no activity in the coronary arteries or the venous system, but it can cause reflex tachycardia and renin-mediated sodium and fluid retention. It has an initial latency of up to 30 minutes after it is given, and its duration of action may be between 4 and 12 hours. Because of its prolonged duration and unpredictability of the effectiveness, it has generally been replaced by newer, faster-acting and more titratable medications.

A remaining advantage of hydralazine is that it can be given intramuscularly, and this may be helpful for the patient requiring urgent treatment who does not yet have an IV line. The initial dose is 0.2 to 0.6mg/kg, up to a maximum dose of 20mg. It is also safe to use in pregnancy, and it had been the first-line therapy in that setting, but it has largely been replaced by labetalol and nicardipine.

Enalaprilat: This agent is the only available angiotensin-converting enzyme (ACE) inhibitor for IV use. There are very few reports of the use of this medication in the pediatric literature, but it appears to lower BP quickly and effectively without causing significant hypotension. It has a relatively slow onset of action (peak effects reached at about 1 hour) and long duration (median of 12 hours in a neonatal case series), it is difficult to titrate to effect.

This along with its potential to precipitate acute kidney injury, especially in the setting of renovascular hypertension, should limit its use to less acute cases of hypertension under the supervision of a specialist. The usual dosage is 5 to 10mcg/kg; onset of action is usually within an hour with duration of action of 4 to 12 hours.

Phentolamine: This agent is a potent adrenergic inhibitor, and it has been used with success in the treatment of hypertensive crises due to pheochromocytoma or in the setting of increased catecholamines, which may be seen in cocaine and amphetamine overdose. Other reasons to use this drug include the patient with pheochromocytoma that develops a hypertensive crisis during radiologic evaluation or in the perioperative period. Onset of action is 1 to 2 minutes with a duration of action of 10 to 30 minutes. The recommended dosage is 0.05 to 0.1mg/kg IV; maximum of 5mg/dose.

IV infused/drip medications

Nitroprusside: This agent is an arterial and venous vasodilator, and it therefore decreases both cardiac preload and afterload. It has a near instantaneous onset of action and a plasma half-life of only several minutes, so it has historically been one of the most commonly used medications for the treatment of hypertensive emergencies and urgencies. It has little or no inotropic or chronotropic effects. Recommendations for dosing start at 0.3 to 0.5mcg/kg/min, titrating upward to the desired effect, with a maximum dose of 8mcg/kg/min. Most patients will respond to rates of infusion of about 3mcg/kg/min.

The product is light sensitive, and it must be protected from light exposure to prevent degradation. Nitroprusside is metabolized by red blood cells (RBCs) to cyanide, and that gets metabolized to thiocyanate in the liver and excreted by the kidneys. In patients with poor renal function or with prolonged use (more than 24 to 48 hours of continuous infusion), there may be accumulation of dangerous levels of cyanide and thiocyanate.

Thiosulfate can be coadministered to limit its toxicity, but given this risk of significant toxicity and the development of other fast-acting agents, its role has largely been relegated to a second-line agent in the management of hypertensive emergency.

Nicardipine: This is a second-generation dihydropyridine calcium channel blocker that may be administered intravenously, and it has a rapid onset of action and brief elimination half-life. It has high selectivity for the vasculature and in particular causes cerebral and coronary vasodilatation with limited myocardial effect, When given as an IV infusion, it can be effectively titrated to achieve BP control. This drug has been widely used in adults for the management of hypertensive emergencies as well as controlled hypotension in spinal surgeries.

There have been multiple case series reporting its use in pediatric patients, and they have been promising. Because it does not share the β-blocker side effect profile with potential to cause bradycardia and bronchospasm, it may be used in place of labetalol or other adrenergic antagonists. It also requires no dosing modifications for patients with kidney failure. A nicardipine infusion should be started at a rate of 1mcg/kg/min and titrated upward to a maximum of 3mcg/kg/min, although doses of 5 to 10 mcg/kg/min have been reported as safe.

There have been reports in adults of increases in intracranial pressure with nicardipine, so its use in the setting of an intracranial mass or another space-occupying lesion is discouraged. Reported adverse effects include hypotension, headache and nausea, as well as reflex tachycardia and phlebitis at the site of the infusion.

Esmolol: This is a short-acting, cardioselective β-adrenergic blocker. Onset of action is under 1 minute, and duration of action is very brief (10 to 20 minutes). It is rapidly metabolized in the bloodstream, and it can be used safely in patients with renal or hepatic compromise. Because of its short time to effect, rapid metabolism and the ability to titrate to the desired effect, it may become more widely used in children. To date, however, its reported use in the literature is primarily limited to postoperative BP control following coarctation repair and other congenital heart diseases.

Esmolol is usually started with a loading dose of 100 to 500mcg/kg, followed by a continuous infusion of 100mcg/kg/min, titrated up to 500mcg/kg/min as needed. Side effects include first-degree heart block, nausea, flushing. Concerns about the side effect profiles of β-blockade in certain populations remain.

Fenoldapam: This is a selective Dopamine 1-receptor agonist. Onset of action is within 15 minutes, and duration of action ranges between 15 and 30 minutes. Because of its effects on the receptors present in the mesenteric, renal, coronary and cerebral arterioles, it has been shown to improve creatinine clearance, urine output and urinary excretion of sodium. This drug may be especially useful in patients with compromised renal function, and the drug is cleared by way of hepatic conjugation so dose adjustment is not necessary with renal insufficiency.

There has been limited use in the pediatric population, but the recommended dosage is 0.5 to 2.0mcg/kg/min, which is higher than that needed in adults. Side effects include headaches and flushing.

3. Diagnosis

Diagnostic criteria

Once the patient is stabilized, establishing a diagnosis will be important to be able to know how to best treat the patient, for prognostic purposes and to establish follow-up care for the patient.

In addition to a complete history including neonatal, birth history and family history, and an examination, there will be a need for some diagnostic testing. This diagnostic testing may require laboratory assessment of blood and urine samples, radiologic evaluations, and sometimes for specific studies such as echocardiography (ECG), more invasive imaging, ambulatory BP monitoring.

There may be evidence of renal disease such as growth failure, hematuria or oliguira. Prior history of insults to the kidneys or urinary tract such as urinary tract infections (especially upper tract infections such as pyelonephritis), posterior urethral valves or other genitourinary tract anomalies, prematurity with placement of an umbilical artery catheter are important to consider. Recent trauma, including head injury, would be important to know. Episodic flushing, tachycardia or weight changes may be signs of an endocrinologic disturbance.

Medication history is important as well. Prescribed medications such as contraceptives, steroids, beta-agonists, stimulant medications, as well as over-the-counter medications (ie, decongestants), dietary supplements, and illicit drugs should all be considered.

A detailed family history of essential hypertension, its complications, kidney disease or other illnesses can be helpful.

Symptoms of target organ damage should be elicited, including visual disturbances, seizures, encephalopathy, or other CNS involvement. Cardiac compromise might be suggested by dyspnea, palpitations, exercise intolerance or syncope.

Physical examination includes a full set of vital signs. An accurate height, weight and calculated body mass index (BMI) are necessary.

Four extremity BPs, or at least a lower extremity BP, is useful to assess for the possibility of coarctation of the aorta. A complete neurologic examination is useful to determine signs of encephalopathy, and fundoscopy can be helpful to look for signs of increased intracranial pressure. Signs of head injury should be assessed, especially in small children.

The cardiac examination should be helpful to assess for signs of cardiac failure, and this would include assessing for hepatomegaly, pulmonary congestion, ventricular hypertrophy with a displaced apical pulse. Examination of distal pulses can also be helpful in the assessment of a possible coarctation as well. The presence of edema (including ascites) or an abdominal bruit may be evidence of underlying renal dysfunction.

Emergently, diagnostic testing usually includes basic testing. In general, one should focus on ruling out the most common forms of hypertension and assessing organ dysfunction. If there is evidence of encephalopathy, congestive heart failure or kidney failure, then there ought to be further diagnostic testing specific to those conditions.

Laboratory evaluation should include a CBC to look for anemia (suggestive of chronic kidney disease) or intravascular hemolysis (hemolytic-uremic syndrome). Urinalysis is helpful to look for hematuria, proteinuria, and any cells or casts. A chemistry panel with electrolytes, blood urea nitrogen (BUN) and creatinine should be checked to look at overall renal function. In the setting of mental status changes, signs of encephalopathy or signs of increased intracranial pressue, a computed tomography (CT) scan of the head should be done.

Adolescent girls should have a pregnancy test. Children with severe hypertension should have an evaluation that includes a chest X-ray and electrocardiogram (ECG) to look for signs of congestive heart failure or myocardial hypertrophy.

After initial testing is done and response to therapy is determined, further specialized diagnostic testing may be necessary. In the setting of possible glomerulonephritis, serologic studies such as complement (especially C3 and C4) levels, antinuclear antibodies, streptococcal antibodies (ASO, antiDNAse B) may be helpful to distinguish possible causes of kidney diseases.

Renal imaging can be helpful as well. Ultrasonography is generally easy to obtain, safe from ionizing radiation, and painless, and it can provide a lot of useful information about the kidneys. Occasionally more specific testing with nuclear medicine studies may be helpful, but those studies are not usually done emergently or urgently. In the setting of suspected catecholamine excess, plasma catecholamines may be sent, and there may be reason to consider collecting urine for urinary metabolites of catecholamines.

ECG is useful to assess cardiac anatomy and to look more sensitively for evidence of target organ disease like left ventricular hypertrophy.

The diagnostic testing should not delay appropriate management of BP in the urgent or emergent situation.

Diagnostic approach

The basic diagnostic approach includes the following:

- A complete history and a full physical examination

- Screening labs

- Baseline imaging: ECG, renal U/S

- More invasive testing based on results of initial testing

4. Specific Treatment

Oral medications

Nifedipine

- Short-acting oral calcium channel blocker

- Sublingual/PO

- Initial dose of 0.25mg/kg and a maximum dose of 10mg

IV intermittently dosed medications

Labetalol

- Combined alpha1 and β-adrenergic receptor blocker

- IV boluses of 0.2 to 1mg/kg are used, and they may be repeated every 10 to 15 minutes.

- Arterial vasodilator; its mechanism of action is not well understood.

- IV/IM (intramuscular)

- Initial dose is 0.2 to 0.6mg/kg, up to a maximum dose of 20mg.

Enalaprilat

- ACE inhibitor

- IV

-0.005 to 0.01mg/kg every 8 to 24 hours

Phentolamine

- Adrenergic inhibitor

- IV

- Recommended dosage is 0.05 to 0.1mg/kg; maximum dose 5mg/dose.

IV infused/drip medications

Nicardipine

- Dihydropyridine calcium channel blocker

- IV infusion

- 0.5 to 3mcg/kg/min

Nitroprusside

- Direct vasodilator

- IV infusion

- 0.5 to 8 mcg/kg/min

Esmolol

- Cardioselective beta-antagonist

- IV infusion

- 50 to 300mcg/kg/min

Fenoldapam

- Dopamine 1-receptor agonist

- IV infusion

- 0.5 to 2mcg/kg/min

Pathophysiology

Severe hypertension can lead to a number of pathologic changes, and there have been well documented changes noted especially in the kidneys. Changes seen grossly in the kidneys include subcapsular petechial hemorrhages that may also involve the renal cortex. At a microscopic level, the glomeruli show fibrinoid necrosis, hemorrhage and patchy inflammation. The renal vasculature also shows changes such as arteriolar fibrinoid necrosis as well as subendothelial plasma insudation.

Other noted pathologic features include marked intimal hyperplasia and proliferative endarteritis of the interlobular arteries, proliferation of intimal cells creating an "onion skin" appearance that may be present in larger blood vessels as well, medial hypertrophy and perivascular fibrosis. Because of these changes, the vessels may become occluded with subsequent renal ischemia.

CNS abnormalities include chronic changes with fibrinoid necrosis of the vasculature, and recent changes caused by acute encephalopathy with breakdown of the blood-brain barrier leading to the transudation of fluid into the brain with resultant edema. There may also be microinfarctions and petechial hemorrhages.

Imaging studies may reveal changes such as white matter hypodensity or edema on CT or increased T2 signaling focally in the cortex and white matter on magnetic resonance imaging (MRI). There is a condition called PRES (occipital parietal encephalopathy) that may have a range of symptoms linked with MRI findings. The clinical symptoms may include headaches, seizures, altered mental status and cortical blindness associated with imaging study (CT, MRI) findings involving the parietal-occipital areas. PRES is reversible with control of the BP.

The biggest pathophysiologic concern related to severe hypertension relates to its impact on vascular autoregulation. The blood flow to the target organs like the kidneys and the CNS is tightly regulated to allow for perfusion across a wide range of pressures. With a drop in BP, there is dilation of the afferent arteriole to maintain renal perfusion, and with increased BP there is arteriolar vasoconstriction to diminish the impact of high pressure on vulnerable target organs.

The changes that are noted anatomically in severe hypertension shift vascular responsiveness, and the rigid vessels act merely as pipes that transmit higher pressures directly on the organs downstream. Conversely, decreases in BP can lead to exaggerated decreases in organ perfusion. There may be loss of compensation with sudden drops in BP, which can cause changes to occur specifically in the "watershed" areas with resulting cerebral infarction, transverse ischemic myelopathy or blindness.

Neonates are particularly vulnerable and at risk for intracranial hemorrhage and other CNS sequelae of acute rises and falls in BP. They not only have poor cerebral autoregulation, but they also have highly vulnerable blood vessels in the subependymal germinal matrix.

Epidemiology

There is some controversy about the degree of BP increase that warrants consideration as an emergency or to be labeled as severe hypertension. Subsequently, there are also few data on which to base decisions about when to initiate the use of antihypertensive medications in this group as well.

There are consensus statements published by the National High Blood Pressure Education Program that are available to assist clinicians in the evaluation and management of hypertension in children and adolescents. The most recent set of guidelines were published in 2004 as The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. This report provides an approach based on the best available evidence, when it is there, and also expert opinion, when evidence is lacking.

In a case series of 110 children with hypertension requiring emergency management, hypertensive retinopathy was present in 27%, hypertensive encephalopathy in 25%, seizures in 25%, left ventricular hypertrophy in 13%, facial palsy in 12%, visual symptoms in 9%, and hemiplegia in 8%. An interesting point made by the authors of that study was that there were 29% of patients with BP levels exceeding the 99th percentile without any target organ damage detected at all.

(These articles provide good background on the definition and scope of the problem of severe hypertension in pediatric patients. They discuss presenting signs and symptoms, approaches to the initial evaluation and management of the condition, and discuss treatment options that are available.)

Epidemiology

(This article is often quoted as a basis for the potential for target organ involvement at the time of presentation.)

Reference articles

"The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents". Pediatrics..
vol. 114. 2004. pp. 555-76.

(This article provides the most recent normative data on BP in children and adolescents with tables that are stratified by age, gender and stature, along with cut-off values for the 50th, 90th, 95th and 99th percentiles of BP.)

Sinaiko, AR, Daniels, SR. "The use of short-acting nifedipine in children with hypertension: another example of rthe need for comprehensive drug testing in children". J Pediatr..
vol. 139. 2001. pp. 7-9.